1. Field of the Invention
This invention concerns an improved long acting sustained release pharmaceutical composition and dosage form for dihydropyridine calcium channel blockers.
2. Description of Related References
Calcium channel blockers are a relatively recently discovered class of compounds which possess a wide spectrum of properties useful in the treatment of cardiovascular and cerebrovascular disorders. Among the clinical applications for which this class of compounds has shown some useful therapeutic properties are the treatment of classic exertional angina, vasospastic angina, angina pectoris, acute myocardial infarction, cardiac arrhythmias, systemic arterial hypertension, pulmonary arterial hypertension, and cardiomyopathies.
Several structural classes of compounds are known which exhibit calcium channel blocking utility. Compounds representative of some of these classes include nicardipine, verapamil, diltiazam, perhexiline and lidoflazine.
The structural class of calcium channel blockers of interest in this invention, of which nicardipine is a member, are 1,4-dihydropyridine-3,5-dicarboxylic acid derivatives of the general formula A: ##STR1## in which AR is a simple or fused aryl or heteroaryl ring moiety; X is hydrogen or one or more substituents on the AR moiety; R.sub.7 and R.sub.8 are independently hydrogen or ester forming moieties; R.sub.9 and R.sub.10 are independently methyl or various other 2 and 6 position substituents on the dihydropyridine ring, and R is hydrogen or an alkyl or simple aryl group. Examples of AR groups include, but are not limited to phenyl, pyridinyl, benzofurazanyl, benzoxadiazolyl and the like. Examples of X groups include, but are not limited to alkyl, halo, haloalkyl, alkoxy, haloalkoxy, alkoxycarbonyl, alkenyl, methylenedioxy, ethylenedioxy, nitro, cyano and the like. Examples of R.sub.7 and R.sub.8 ester forming moieties include, but are not limited to alkyl, alkoxy, haloalkyl, nitro, hydroxyalkyl, alkylenyloxyalkyl, phenylaminoalkyl, alkylaminoalkyl or alkoxyaminoalkyl, amino(carbonyl)oxyalkyl, or an optionally substituted simple or fused aryl, aralkyl or arylsulfonyl group such as, but not limited to, phenyl, phenylalkyl, phenylsulfonyl, phenylalkenyl, naphthyl, naphthylalkyl, dioxaphosphorinanyl, piperidinyl, pyrrolidinyl, furyl, pyrrolyl, pyridyl, imidazolyl, thienyl, morpholinyl, [(tetrahydropyran-2-yloxy)-alkyl]phenoxyalkyl or [(tetrahydropyran-2-yloxy)-alkyl]phenylthioalkyl. Examples of R.sub.9 and R.sub.10 substituents include, but are not limited to alkyl such as methyl, a substituted alkyl group such as hydroxyalkyl or aminoalkoxyalkyl, cyano, or optionally substituted phenylcarbonylalkyl; Examples of R groups other than hydrogen include, but are not limited to alkyl, benzyl, morpholinyl and morpholinylalkyl.
Many compounds within the general class represented by formula A are known and have been shown to have calcium channel blocking activity. It is known, for example, that 4-(2'-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester shows calcium channel blocking activity (U.S. Pat. No. 3,644,627). Other compounds within this structural and pharmacologic class include those disclosed in U.S. Pat. No. 3,511,837 (4-pyrimidyl-1,4-dihydropyridine derivatives), U.S. Pat. No. 3,691,177 (cyanophenyl-1,4-dihydropyridine derivatives), German Offlegungsschrift No. 1,813,436 (N-alkyl-1,4-dihydropyridine derivatives), No. 1,963,185 (4-nitro and other group substituted phenyl-1,4-dihydropyridine derivatives), No. 1,963,186 (sulfur containing 4-aryl-1,4-dihydropyridine derivatives), No. 2,005,116 (1,4-dihydropyridine-3,5-dicarboxylic acid unsaturated alkyl esters), No. 2,3,146 (3-alkanoyl-1,4-dihydropyridine-5-carboxylic acid esters, U.S. Pat. No. 3,511,837 (1,4-dihydro-2,6-dimethyl-4-(2'-trifluoromethylphenyl)-3,5-pyridine dicarboxylic acid diethyl ester) and in BE 862-107, U.S. Pat. No. 4,017,629, DE 2,616,995, and German Offenlegungsschrift 3,501,695 (various 3-arylsulfonyl 1,4-dihydropyridine derivatives). Other 1,4-dihydropyridine compounds with cardiovascular activity are disclosed in U.S. Pat. Nos. 3,644,627 and 3,485,847, in German Offenlegungsschrift 1,670,827 and in Bundesrepublik Deutschland Auslegeschrift 17,92,764.
Specific compounds of formula A which can be incorporated in the long acting sustained release composition of this invention include 2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-[3-(4-[2-(tetrahydropyran- 2-yloxy)ethyl]phenoxy)propoxy carbonyl]-1,4-dihydropyridine disclosed in U.S. application Ser. No. 874,264 filed Jun. 13, 1986, now U.S. Pat. No. 4,761,420 issued Aug. 2, 1988, the disclosure of which is incorporated by reference herein; 3,5-pyridinedicarboxylic acid, 2-[(2-aminoethoxy)methyl]-4-(2-chlorophnyl)-1,4-dihydro-6-methyl, 3-ethyl 5-methyl ester, (.+-.)-, (Z)-2-butenedioate, generic name: amlodipine; 3,5-pyridinedicarboxylic acid 4-(4-benzofurazanyl)-1,4-dihydro-2,6-dimethyl-, diethyl ester, generic name: darodipine; 3,5-pyridinedicarboxylic acid, 1,4-dihydro-2,6-dimethyl-1-[2-(4-morpholinyl)ethyl]-4-[2-(trifluoromethyl) phenyl]-, diethyl ester, generic name: flordipine; 1,4-dihydro-2,6-dimethyl-4-(2-trifluoromethyl-phenyl)-3,5-pyridinedicarbox ylic acid 2-([1-(4-hydroxyphenyl)-3-oxopropyl]amino)ethyl ester), generic name: iodipine; isopropyl methyl 4-(4-benzofurazanyl)-1,4 -dihydro-2,6-dimethyl-3,5-pyridine dicarboxylate, generic name: isodipine; diethyl 1',4'-dihydro-2',6'-dimethyl-2-(methylthio)[3,4'bipyridine]-3'5'-dicarboxy late, generic name: mesudipine; 3,5 pyridinedicarboxylc acid, 2-cyano-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-, 3-methyl 5-(1-methylethyl) ester, generic name; nilvadipine; ethyl methyl 1,4-dihydro-2,6-dimethyl-4-[2,3-(methylenedioxy)-phenyl-3,5-pyridinedicarb oxylate, generic name: oxodipine; dimethyl 4-[o-(di-fluoromethyl)phenyl]-1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylate, generic name: riodipine; methyl 2,6-dimethyl-4-(2-nitrophenyl)-5-(2-oxo-1,3,2-dioxaphosphorinan-2-yl)-1,4- dihydropyridine 3-carboxylate; 1,4-dihydro-2-hydroxmethyl-4-(m-nitrophenyl)-6-methyl-3,5-pyridine dicarboxylic acid diethyl ester; methyl (E)-3-phenyl- 2-propeny-1-yl-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dica rboxylate; (E)-4-(2-(3-(1,1-dimethylethoxy)-3-oxo-1-propenyl)phenyl-1,4-dihydro-2,6-d imethyl-3,5-pyridinedicarboxylic acid, diethyl ester; 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid methyl 1-(phenylmethyl)-3-piperidinyl ester monohydrochloride; 3-(2-furoyl)-5-methoxycarbonyl-2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydrop yridine; 3,5-pyridinedicarboxylic acid 2-(((aminocarbonyl)oxy)methyl)-4-(2,3-dichlorophenyl)-1,4-dihydro-6-methyl -5-methyl 3-(1-methylethyl)ester; 1-benzyl-3-pyrrolidinyl methyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate; and isopropyl 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-2,6-dimethyl-5-nitro-3-pyridineca rboxylate.
Calcium channel blockers of particular interest in this invention are compounds selected from the group represented by the formula: ##STR2## where;
R.sub.1 is --NO.sub.2, --CF.sub.3, or halo;
R.sub.2 is alkyl or --CH.sub.2 CH.sub.2 OCH.sub.3 ; and
R.sub.6 is hydrogen or alkyl; and
R.sub.3 is alkyl, alkylenyloxyalkyl, haloalkyl, optionally substituted phenyl alkyl, optionally substituted napthyl alkyl, or ##STR3## in which:
A is alkylene;
R.sub.4 is alkyl, alkoxy, or optionally substituted phenyl or phenyl alkyl; and
R.sub.5 is hydrogen or alkyl;
and the pharmaceutically acceptable salts thereof.
Several compounds within this group are known to possess a high degree of calcium channel blocking activity. These include, for example, 4-(2'-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester, generic name: nifedipine (U.S. Pat. No. 3,644,627); 4-(3'-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid di-n-propyloxethyl ester, generic name: niludipine; 4-(3'-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-ethyl ester 5-methyl ester, generic name: nitrendipine; 4-(3'-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl ester 5-(2-methoxyethyl)ester, generic name: nimodipine; 4-(2'-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl ester 5-isobutyl ester, generic name: nisoldipine; 4-(2',3'-dichloro)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-ethyl ester 5-methyl ester, generic name: felodipine; 4-(3'-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl ester 5-.beta.-(N-benzyl-N-methylamino)-ethyl ester, generic name: nicardipine; isopropyl methyl 1,4-dihydro-2,6-dimethyl 4-(3-nitrophenyl)-3,5 -pyridine dicarboxylate; and 2,6-dimethyl-3,5-diethoxycarbonyl-4-(o-difluoromethylphenyl)-1,4-dichydrop yridine.
Other compounds of Formula I which can be practically administered from the long acting sustained release compositions of this invention include 2,6-dimethyl-3,5-bis(methoxycarbonyl)-4-phenyl-1,4-dihydropyridine, 2,6-dimethyl-3,5-bis(methoxycarbonyl)-4-(3-methylphenyl)-1,4-dihydropyridi ne, 2,6-dimethyl-3,5-bis(methoxycarbonyl)-4-(3-cyanophenyl)-1,4-dihydropyridin e, 2,6-dimethyl-3,5-bis(methoxycarbonyl)-4-(3-nitrophenyl)-1,4-dihydropyridin e, 2,6-dimethyl-3,5-bis(methoxycarbonyl)-4-(4-nitrophenyl)-1,4-dihydropyridin e, 2,6-dimethyl-3,5-bis(methoxycarbonyl)-4-(4-methylphenyl)-1,4-dihydropyridi ne,2,6-dimethyl-3,5-bis(methoxycarbonyl)-4-[4-(dimethylamino)phenyl]-1,4-di hydropyridine, 2,6-dimethyl-4-phenyl-1,4-dihydropyridine 3,5-dicarboxylacid diethyl ester, 2,6-dimethyl-3,5-bis(methoxycarbonyl)-4-(2,4-dinitrophenyl)-1,4-dihydropyr idine, 2,6-dimethyl-3,5-bis(methoxycarbonyl)-4-[2-(trifluoromethyl)phenyl)-1,4-di hydropyridine, and 2,6-dimethyl-3,5-bis(methoxycarbonyl)-4-(pentafluorophenyl)-1,4-dihydropyr idine, all of which are disclosed in J. Med. Chem (1986) 29 (12), pp. 2504-2511.
Calcium channel blockers of the 1,4-dihydropyridine class share a number of pharmacological and pharmacokinetic properties in common which render them well suited to administration by the long acting sustained release methods of this invention. They are drugs which are extensively lipid-soluble and therefore are widely and extensively distributed within body tissues at steady state. They are also rapidly absorbed after oral administration, showing peak plasma levels within approximately about one hour (T.sub.max). The half-life of elimination of these compounds is generally in the range of two to five hours, thus necessitating administration of standard oral dosage forms three to four times daily.
Additionally, some of the compounds, in particular, nicardipine, undergo extensive first pass metabolism.
The pharmaceutical compositions and dosage forms of this invention are particularly well suited for the administration of nicardipine and its pharmaceutically acceptable salts, such as nicardipine and hydrochloride. The preparation and use of nicardipine and other closely related compounds and their pharmaceutically acceptable salts are described in U.S. Pat. No. 3,985,758, the disclosure of which is incorporated by reference herein.
At the present time, the preferred route of administration for most therapeutic applications of the dihydropyridine calcium channel blockers is via an oral dosage form. These are typically compressed tablets, hard gelatin capsules filled with a powder mix, or soft gelatin capsule filled with a solution, and are conventionally administered three or four times daily.
However, conventional release oral dosage forms are poorly suited to dihydropyridine calcium channel blocker therapy. At the low pH that often occurs in the stomach, the solubility of the basic dihydropyridines is relatively high, resulting in rapid dissolution and absorption. At higher gastro-intestinal pH values, dihydropyridine solubility, and hence the dissolution rate, decreases. As a result, conventional release oral dosage forms release calcium channel blocker more rapidly in the more acidic regions and less rapidly in the less acidic regions of the gastrointestinal tract. The release profiles of such dosage forms are inherently dependent upon the local pH.
There is a need, therefore, for a long acting dosage form with sustained release properties capable of providing therapeutic calcium channel blocker plasma concentrations when the dosage form is administered less frequently, preferably once or twice daily. In addition to providing convenience for the patient, such a sustained release dosage form would minimize undesirable fluctuations in drug plasma concentration.
In Kawata et al., U.S. Pat. No. 4,343,789, formulations and dosage forms for nicardipine and related compounds are described which provide some dissolution control, and hence sustained release of the drug. As described in the patent, there is formed a powder containing amorphous nicardipine, polyethylene oxide, and other excipients which can then be formed into granules, tablets, pills or capsules by conventional means. The formulation requires that the nicardipine or salt thereof be in amorphous form, and be combined with polyethylene oxide in a fine particle powder or granules. The formulation may additionally contain a pH-dependent agent for dissolution control, such as a copolymer of methacrylic acid and a methacrylic acid ester. While the specific disclosure is primarily directed to tablet formulations, one capsule dosage form is disclosed (in Example 9) which contains small coated pills obtained by film coating a mixed powder containing nicardipine hydrochloride with a solution of methyl cellulose in water, and then further coating part of the coated pills with an organic solution of Eudragit (methacrylic acid/methyacrylic acid ester copolymer).
However, the preparation of the drug in amorphous form and the incorporation of polyoxyethylene are time consuming and expensive manufacturing procedures. Other granular and particulate calcium channel blocker compositions formulated with a pH-dependent binding agent are known. However, the manufacture of these compositions has required the use of an organic solvent, which must subsequently be removed by arduous and lengthy drying procedures and always leaving the risk of toxic residues.
Ludwig, U.S. Pat. No. 4,665,100, discloses a method of formulating a synthetic drug for use in a feed which will reduce the carryover of the drug from one lot of feed to a subsequent lot in feed mill operations. The patented process involves intimately mixing the drug (about 1-40% of minigranule on a dry weight basis) with a carrier (50-98% on a dry weight basis), a physiologically acceptable binder (about 1-10% on a dry weight basis), and water, extruding the mixture through a perforated plate having relatively small apertures (about 0.5-1.5 mm) into elongated strands of extrudate, and contacting the elongated strands of extrudate with a moving frictional plate, imparting motion to said extrudate and developing a tumbling, rolling bed thereof wherein the strands are reduced to nearly spherical particals, called minigranules, drying them to remove excess moisture, and seiving the minigranules through meshed wire screens to obtain desired particle size.
Sugimoto et al., U.S. Pat. No. 4,765,990 (Aug. 23, 1988), disclose a sustained-release preparation containing nifedipine which comprises a Composition A and Composition B in a ratio of 15:85 to 50:50 by weight of nifedipine. Composition A is a rapid-release preparation containing as an active ingredient nifedipine fine powder of not more than 5 microns. Composition B is a delayed-release preparation containing as the active ingredient nifedipine fine powder having an average particle size of not more than 5 microns and having a surface coating layer comprising a non-toxic, hardly water-soluble substance and an enteric high molecular compound.
EP 0,267,386 (Derwent Abstract 88-134312/20) discloses solid, sustained release nifefipine dosage forms comprising, nifedipine and low-viscosity ethyl cellulose on a carrier comprising a hydroxyalkyl cellulose, a sugar and starch.
There is disclosed in U.S. Ser. No. 057,469 filed Jul. 26, 1987, now U.S. Pat. No. 4,940,596, owned in common by the assignee of this application for patent, a composition which was conceived for the purpose to overcome some of what were perceived as disadvantages or deficiencies of the references mentioned above, particularly with respect to Kawata et al., U.S. Pat. No. 4,343,789. The composition of the above-mentioned patent application comprises essentially spherical, non-coated, non-rugose particles having diameters up to 1.2 mm, comprising an effective amount of a calcium channel blocker in intimate admixture with at least 3 weight percent of a pH-dependent binder which is less soluble at lower pH and more soluble at higher pH. This composition provides therapeutic plasma concentrations of calcium channel blocker suitable for twice daily administration of the pharmaceutical composition.
Although the pharmaceutical composition described in the preceding paragraph is quite useful and effective and represents an improvement over the art described in the foregoing passages, there remains a need for a pharmaceutical composition which (1) provides therapeutically effective dihydropyridine calcium channel blocker plasma levels when administered even less frequently than twice daily, (2) avoids the risk of the phenomenon of "dose dumping," which is essential at the higher doses given once daily (3) provides readily and economically manufacturable drug-containing particles of substantially uniform and regular size and shape suitable for incorporation in hard gelatin capsules and other oral and parenteral dosage forms and uses the thermodynamically stable powder form of the drug thereby avoiding the inherent physical stability and consequent changing bioavailability of a thermodynamically unstable amorphous form.